Interleukin-17 promotes prostate cancer via MMP7-induced epithelial-to-mesenchymal transition.

Abstract

Chronic inflammation has been associated with a variety of human cancers including prostate cancer. Interleukin-17 (IL-17) is a critical pro-inflammatory cytokine, which has been demonstrated to promote development of prostate cancer, colon cancer, skin cancer, breast cancer, lung cancer and pancreas cancer. IL-17 promotes prostate adenocarcinoma with a concurrent increase of matrix metalloproteinase 7 (MMP7) expression in mouse prostate. Whether MMP7 mediates IL-17's action and the underlying mechanisms remain unknown. We generated Mmp7 and Pten double knockout (KO) (Mmp7-/-) mouse model and demonstrated that MMP7 promotes prostate adenocarcinoma through induction of epithelial-to-mesenchymal transition (EMT) in Pten-null mice. MMP7 disrupted E-cadherin/β-catenin complex to upregulate EMT transcription factors in mouse prostate tumors. IL-17 receptor C and Pten double KO mice recapitulated the weak EMT characteristics observed in Mmp7-/- mice. IL-17 induced MMP7 and EMT in human prostate cancer LNCaP, C4-2B and PC-3 cell lines, while small interfering RNA knockdown of MMP7 inhibited IL-17-induced EMT. Compound III, a selective MMP7 inhibitor, decreased development of invasive prostate cancer in Pten single KO mice. In human normal prostates and prostate tumors, IL-17 mRNA levels were positively correlated with MMP7 mRNA levels. These findings demonstrate that MMP7 mediates IL-17's function in promoting prostate carcinogenesis through induction of EMT, indicating IL-17-MMP7-EMT axis as a potential target for developing new strategies in the prevention and treatment of prostate cancer.

• Authors: Q Zhang, S Liu, K R Parajuli, W Zhang, K Zhang, Z Mo, J Liu, Z Chen, S Yang, A R Wang, L Myers, Z You
• Journal: Oncogene (Oncogene) Vol. 36 Issue 5 Pg. 687-699 (02 02 2017) ISSN: 1476-5594 [Electronic] England
• PMID: 27375020 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Interleukin-17
• Matrix Metalloproteinase 7

Topics

• Animals
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition
• Humans
• Inflammation (pathology)
• Interleukin-17 (metabolism)
• Male
• Matrix Metalloproteinase 7 (metabolism)
• Mice
• Prostatic Neoplasms (metabolism, pathology)
• Signal Transduction